Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, 94158, USA.
VA Medical Center Endocrine Unit and Bone Imaging Core Facility, University of California San Francisco, San Francisco, CA, 94158, USA.
Nat Commun. 2019 Jan 11;10(1):163. doi: 10.1038/s41467-018-08046-4.
Central estrogen signaling coordinates energy expenditure, reproduction, and in concert with peripheral estrogen impacts skeletal homeostasis in females. Here, we ablate estrogen receptor alpha (ERα) in the medial basal hypothalamus and find a robust bone phenotype only in female mice that results in exceptionally strong trabecular and cortical bones, whose density surpasses other reported mouse models. Stereotaxic guided deletion of ERα in the arcuate nucleus increases bone mass in intact and ovariectomized females, confirming the central role of estrogen signaling in this sex-dependent bone phenotype. Loss of ERα in kisspeptin (Kiss1)-expressing cells is sufficient to recapitulate the bone phenotype, identifying Kiss1 neurons as a critical node in this powerful neuroskeletal circuit. We propose that this newly-identified female brain-to-bone pathway exists as a homeostatic regulator diverting calcium and energy stores from bone building when energetic demands are high. Our work reveals a previously unknown target for treatment of age-related bone disease.
中枢雌激素信号协调能量消耗、生殖，并且与外周雌激素共同影响女性骨骼的动态平衡。在这里，我们在中脑基底下丘脑中敲除雌激素受体 alpha（ERα），仅在雌性小鼠中发现了一种强大的骨骼表型，导致异常强壮的小梁骨和皮质骨，其密度超过其他报道的小鼠模型。立体定向引导的弓状核中 ERα 的缺失增加了完整和去卵巢雌性小鼠的骨量，证实了雌激素信号在这种性别依赖性骨表型中的中心作用。在表达 kisspeptin（Kiss1）的细胞中敲除 ERα 足以重现骨表型，确定 Kiss1 神经元是这个强大的神经骨骼回路中的一个关键节点。我们提出，这个新发现的女性脑骨途径是一种稳态调节剂，当能量需求较高时，它会将钙和能量储存从骨骼构建中转移出来。我们的工作揭示了一个以前未知的治疗与年龄相关的骨骼疾病的靶点。
